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By Rebecca Bromelkamp / Mayo Clinic
PHOENIX — Mayo Clinic researchers and collaborators have identified a previously unrecognized way lung tumors weaken the immune system, helping explain why many patients do not respond to immunotherapy and pointing to a potential new approach to make those treatments more effective.
The study, published in Cancer Immunology Research, focuses on regulatory T cells, immune cells that normally keep the immune system from becoming overactive. In lung cancer, researchers found these same cells can be redirected to protect the tumor instead of the body.
“What we are seeing is the tumor taking advantage of a normal immune safety mechanism and turning it to its own benefit,” says Henrique Borges da Silva, Ph.D., an immunologist at Mayo Clinic in Arizona and senior author of the study. “The same cells that normally prevent immune damage are instead protecting the tumor.”
Lung cancer is the leading cause of cancer-related deaths worldwide. Although immunotherapies have improved outcomes for some patients, many tumors continue to grow because immune cells cannot function effectively inside the tumor environment.
To better understand why, the researchers analyzed patient data from non-small cell lung cancer. They found that regulatory T cells inside lung tumors expressed high levels of P2RX7, and higher P2RX7 expression was linked to worse survival outcomes.
P2RX7 allows regulatory T cells to sense ATP, a molecule released by stressed cells and commonly found at high levels inside tumors. When these cells detect ATP, they accumulate within lung tumors and suppress immune cells that would otherwise attack the cancer.
When P2RX7 was removed from regulatory T cells, lung tumors grew more slowly because the immune system was less suppressed. Immune cells that attack cancer were able to move into tumors more easily and were more active.
The study also found that P2RX7 helps regulatory T cells produce CTLA-4, a molecule that dampens immune responses. Without P2RX7, these regulatory cells were less effective at shutting down immune activity inside lung tumors.
Blocking P2RX7 also helped immune cells work more closely with B cells. This led to higher levels of antibodies that target tumors and to the formation of organized immune cell groups inside tumors, which have been associated with better outcomes in lung cancer.
“If we want immunotherapy to reach more patients, we have to understand why it fails,” Dr. Borges da Silva says. “This study identifies one of the mechanisms standing in the way.”
The researchers also tested a drug that inhibits P2RX7. They found that the inhibitor developed smaller lung tumors in models and had fewer regulatory T cells inside the tumors. While the drug is not yet approved for cancer treatment, the findings suggest it could one day be used alongside existing immunotherapies.
Researchers say more studies are needed before the findings can be tested in patients, but the work highlights how targeting immune suppression inside tumors could help make cancer treatments more effective.
For a full list of authors and disclosures, see the paper.
Information source: Mayo Clinic
